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1.
Brain Behav Immun ; 110: 348-364, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36940752

RESUMO

Insulin growth factor-1 (IGF-1), an osteoclast-dependent osteolysis biomarker, contributes to metastatic bone cancer pain (MBCP), but the underlying mechanism is poorly understood. In mice, the femur metastasis caused by intramammary inoculation of breast cancer cells resulted in IGF-1 increase in femur and sciatic nerve, and IGF-1-dependent stimulus/non-stimulus-evoked pain-like behaviors. Adeno-associated virus-based shRNA selective silencing of IGF-1 receptor (IGF-1R) in Schwann cells, but not in dorsal root ganglion (DRG) neurons, attenuated pain-like behaviors. Intraplantar IGF-1 evoked acute nociception and mechanical/cold allodynia, which were reduced by selective IGF-1R silencing in DRG neurons and Schwann cells, respectively. Schwann cell IGF-1R signaling promoted an endothelial nitric oxide synthase-mediated transient receptor potential ankyrin 1 (TRPA1) activation and release of reactive oxygen species that, via macrophage-colony stimulating factor-dependent endoneurial macrophage expansion, sustained pain-like behaviors. Osteoclast derived IGF-1 initiates a Schwann cell-dependent neuroinflammatory response that sustains a proalgesic pathway that provides new options for MBCP treatment.


Assuntos
Neoplasias Ósseas , Dor do Câncer , Camundongos , Animais , Fator de Crescimento Insulin-Like I/metabolismo , Dor/metabolismo , Hiperalgesia/metabolismo , Células de Schwann/metabolismo
2.
Br J Pharmacol ; 180(9): 1232-1246, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36494916

RESUMO

BACKGROUND AND PURPOSE: The pro-algesic transient receptor potential ankyrin 1 (TRPA1) channel, expressed by a subpopulation of primary sensory neurons, has been implicated in various pain models in mice. However, evidence in rats indicates that TRPA1 conveys nociceptive signals elicited by channel activators, but not those associated with tissue inflammation or nerve injury. Here, in rats, we explored the TRPA1 role in mechanical allodynia associated with stimulation of peptidergic primary sensory neurons (neurogenic inflammation) and moderate (partial sciatic nerve ligation, pSNL) or severe (chronic constriction injury, CCI) sciatic nerve injury. EXPERIMENTAL APPROACH: Acute nociception and mechanical hypersensitivity associated with neurogenic inflammation and sciatic nerve injury (pSNL and CCI) were investigated in rats with TRPA1 pharmacological antagonism or genetic silencing. TRPA1 presence and function were analysed in cultured rat Schwann cells. KEY RESULTS: Hind paw mechanical allodynia (HPMA), but not acute nociception, evoked by local injection of capsaicin or allyl isothiocyanate, the TRP vanilloid 1 (TRPV1) or the TRPA1 activators was mediated by CGRP released from peripheral sensory nerve terminals. CGRP-evoked HPMA was sustained by a ROS-dependent TRPA1 activation, probably in Schwann cells. HPMA evoked by pSNL, but not that evoked by CCI, was mediated by ROS and TRPA1 without the involvement of CGRP. CONCLUSIONS AND IMPLICATIONS: As found in mice, TRPA1 mediates mechanical allodynia associated with neurogenic inflammation and moderate nerve injury in rats. The channel contribution to mechanical hypersensitivity is a common feature in rodents and might be explored in humans.


Assuntos
Doenças do Sistema Nervoso Periférico , Canais de Potencial de Receptor Transitório , Humanos , Ratos , Camundongos , Animais , Hiperalgesia , Canal de Cátion TRPA1 , Inflamação Neurogênica , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Espécies Reativas de Oxigênio
3.
Nucleic Acids Res ; 50(D1): D231-D235, 2022 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-34893873

RESUMO

The MODOMICS database has been, since 2006, a manually curated and centralized resource, storing and distributing comprehensive information about modified ribonucleosides. Originally, it only contained data on the chemical structures of modified ribonucleosides, their biosynthetic pathways, the location of modified residues in RNA sequences, and RNA-modifying enzymes. Over the years, prompted by the accumulation of new knowledge and new types of data, it has been updated with new information and functionalities. In this new release, we have created a catalog of RNA modifications linked to human diseases, e.g., due to mutations in genes encoding modification enzymes. MODOMICS has been linked extensively to RCSB Protein Data Bank, and sequences of experimentally determined RNA structures with modified residues have been added. This expansion was accompanied by including nucleotide 5'-monophosphate residues. We redesigned the web interface and upgraded the database backend. In addition, a search engine for chemically similar modified residues has been included that can be queried by SMILES codes or by drawing chemical molecules. Finally, previously available datasets of modified residues, biosynthetic pathways, and RNA-modifying enzymes have been updated. Overall, we provide users with a new, enhanced, and restyled tool for research on RNA modification. MODOMICS is available at https://iimcb.genesilico.pl/modomics/.


Assuntos
Bases de Dados de Ácidos Nucleicos , Enzimas/genética , RNA/genética , Ribonucleosídeos/genética , Interface Usuário-Computador , Sequência de Bases , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Gráficos por Computador , Bases de Dados de Proteínas , Conjuntos de Dados como Assunto , Enzimas/metabolismo , Gastroenteropatias/genética , Gastroenteropatias/metabolismo , Gastroenteropatias/patologia , Doenças Hematológicas/genética , Doenças Hematológicas/metabolismo , Doenças Hematológicas/patologia , Humanos , Internet , Transtornos Mentais/genética , Transtornos Mentais/metabolismo , Transtornos Mentais/patologia , Doenças Musculoesqueléticas/genética , Doenças Musculoesqueléticas/metabolismo , Doenças Musculoesqueléticas/patologia , Mutação , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , RNA/metabolismo , Processamento Pós-Transcricional do RNA , Ribonucleosídeos/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo
4.
RNA ; 27(4): 367-389, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33376192

RESUMO

RNA modifications have recently emerged as a widespread and complex facet of gene expression regulation. Counting more than 170 distinct chemical modifications with far-reaching implications for RNA fate, they are collectively referred to as the epitranscriptome. These modifications can occur in all RNA species, including messenger RNAs (mRNAs) and noncoding RNAs (ncRNAs). In mRNAs the deposition, removal, and recognition of chemical marks by writers, erasers and readers influence their structure, localization, stability, and translation. In turn, this modulates key molecular and cellular processes such as RNA metabolism, cell cycle, apoptosis, and others. Unsurprisingly, given their relevance for cellular and organismal functions, alterations of epitranscriptomic marks have been observed in a broad range of human diseases, including cancer, neurological and metabolic disorders. Here, we will review the major types of mRNA modifications and editing processes in conjunction with the enzymes involved in their metabolism and describe their impact on human diseases. We present the current knowledge in an updated catalog. We will also discuss the emerging evidence on the crosstalk of epitranscriptomic marks and what this interplay could imply for the dynamics of mRNA modifications. Understanding how this complex regulatory layer can affect the course of human pathologies will ultimately lead to its exploitation toward novel epitranscriptomic therapeutic strategies.


Assuntos
Doenças Metabólicas/genética , Neoplasias/genética , Doenças do Sistema Nervoso/genética , Processamento Pós-Transcricional do RNA , RNA Mensageiro/genética , RNA não Traduzido/genética , Apoptose/genética , Ciclo Celular/genética , Epigênese Genética , Marcadores Genéticos , Humanos , Doenças Metabólicas/metabolismo , Doenças Metabólicas/patologia , Neoplasias/metabolismo , Neoplasias/patologia , Doenças do Sistema Nervoso/metabolismo , Doenças do Sistema Nervoso/patologia , RNA Mensageiro/metabolismo , RNA não Traduzido/metabolismo
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